Methods to incorporate non-natural functional groups into nucleic acids have played a critical role in experiments to elucidate their structure and function. To augment these methods, this project will develop a novel approach to incorporate a large variety of substituents into synthetic oligonucleotides. This design features the use of a 2'-deoxyribofuranose-1'-carboxylic acid as a nucleoside mimic. Amino-substituted compounds can be covalently coupled to this nucleoside derivative either before or after oligonucleotide synthesis. The former requires the synthesis of the corresponding phosphoramidite monomer that can be used in standard solid phase oligonucleotide synthesis. The latter scheme obviates the need for the syntheses of separate monomers for each new derivative but requires development of the conjugation chemistry. When incorporated in oligodeoxyribonucleotides in the place of natural nucleosides, these residues will produce functionalized DNA s where the modification can be introduced at any nucleoside position, the appended group is spatially restricted, and the group can be placed in intimate contact with the stacked DNA bases (i.e., intercalated). Because of the similarity of this design to the structure of natural nucleosides, a number of these derivatives may be incorporated into structures such as double helices with relatively little distortion. This combination of properties, combined with the ease and generality of the synthesis, will yield a unique system to examine problems in nucleic acid chemistry. The results of this project will determine to scope and limitations of this design in such applications.